Apparatus and method for piercing skin with microprotrusions

ABSTRACT

A method and device are described for applying a microprotrusion member ( 44 ) including a plurality of microprotrusions ( 90 ) to the stratum corneum with impact. The method and device are used to improve transport of an agent across the skin for agent delivery or sampling. The applicator ( 10, 60, 80 ) causes the microprotrusion member ( 44 ) to impact the stratum corneum with a certain amount of impact determined to effectively pierce the skin with the microprotrusions ( 90 ). The preferred applicator ( 10, 60, 80 ) impacts the stratum corneum with the microprotrusion member ( 44 ) with an impact of at least 0.05 joules per cm 2  of the microprotrusion member ( 44 ) in 10 msec or less.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Division of application Ser. No. 09/976,798, filedOct. 12, 2001 now U.S. Pat. No. 7,131,960.

TECHNICAL FIELD

The invention relates to an apparatus and method for applying apenetrating member to the stratum corneum by impact, and moreparticularly, the invention relates to the use of an applicator deviceproviding an impact to reproducibly penetrate the stratum corneum with amicroprotrusion array for delivery or sampling of an agent.

BACKGROUND ART

Interest in the percutaneous or transdermal delivery of peptides andproteins to the human body continues to grow as the number of medicallyuseful peptides and proteins becoming increasingly available in largequantities and pure form. The transdermal delivery of peptides andproteins still faces significant problems. In many instances, the rateof delivery or flux of polypeptides through the skin is insufficient,due to their large size and molecular weight, to produce a desiredtherapeutic effect. In addition, polypeptides and proteins are easilydegraded during and after penetration into the skin and prior toreaching target cells. Likewise, the passive transdermal flux of manylow molecular weight compounds is too low to be therapeuticallyeffective.

One method of increasing the transdermal delivery of agents relies onutilizing a skin permeation enhancer, either by pretreatment of the skinor co-delivering it with the beneficial agent. A permeation enhancersubstance, when applied to a body surface through which the agent isdelivered, enhances the transdermal flux of the agent. These enhancerswork may function increasing the permselectivity and/or permeability ofthe body surface, and/or reducing the degradation of the agent.

Another method of increasing the agent flux involves the application ofan electric current across the body surface referred to as“electrotransport.” “Electrotransport” refers generally to the passageof a beneficial agent, e.g., a drug or drug precursor, through a bodysurface, such as skin, mucous membranes, nails, and the like. Thetransport of the agent is induced or enhanced by the application of anelectrical potential, which results in the flow of electric current,which delivers or enhances delivery of the agent. Electrotransportdelivery generally increases agent delivery and reduces polypeptidedegradation during transdermal delivery.

There also have been many attempts to mechanically penetrate or disruptthe skin in order to enhance the transdermal flux, such as, U.S. Pat.No. 5,879,326 issued to Godshall, et al., U.S. Pat. No. 3,814,097 issuedto Ganderton, et al., U.S. Pat. No. 5,279,544 issued to Gross, et al.,U.S. Pat. No. 5,250,023 issued to Lee, et al., U.S. Pat. No. 3,964,482issued to Gerstel, et al., Reissue 25,637 issued to Kravitz, et al., andPCT Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718,WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO98/00193, WO 99/64580, WO 98/28037, WO 98/29298, and WO 98/29365. Thesedevices use piercing elements of various shapes and sizes to pierce theoutermost layer (i.e., the stratum corneum) of the skin. The penetratingelements disclosed in these references generally extend perpendicularlyfrom a thin, flat member, such as a pad or sheet. The penetratingelements, often referred to as microblades, are extremely small in somedevices. Some of these microblades have dimensions (i.e., a microbladelength and width) of only about 25-400 μm and a microblade thickness ofonly about 5-50 μm. Other penetrating elements are hollow needles havingdiameters of about 10 μm or less and lengths of about 50-100 μm. Thesetiny stratum corneum piercing/cutting elements are meant to makecorrespondingly small microslits/microcuts in the stratum corneum forenhanced transdermal agent delivery, or for enhanced transdermal effluxof a body analyte, therethrough. The perforated skin provides improvedflux for sustained agent delivery or sampling through the skin. In manyinstances, the microslits/microcuts in the stratum corneum have a lengthof less than 150 μm and a width which is substantially smaller thantheir length.

When microprotrusion arrays are used to improve delivery or sampling ofagents through the skin, consistent, complete, and repeatablepenetration of the skin by the microprotrusions is desired. Manualapplication of a skin patch including microprotrusions often results insignificant variation in puncture depth across the microprotrusionarray. In addition, manual application results in large variations inpuncture depth between applications due to the manner in which the userapplies the array. Accordingly, it would be desirable to be able toapply a microprotrusion array to the stratum corneum with an automaticor semi-automatic device which provides microprotrusion skin penetrationin a consistent and repeatable manner.

It would be desirable to provide an applicator for consistent andrepeatable application of a microprotrusion array to the skin with theapplicator applying an impact capable of achieving effective penetrationof the stratum corneum with the microprotrusion array.

DISCLOSURE OF THE INVENTION

The present invention relates to a method and device for applying amicroprotrusion member including a plurality of microprotrusions to thestratum corneum with impact. Piercing the skin with the microprotrusionsis used to improve transport of an agent across the skin. The applicatorcauses the microprotrusion member to impact the stratum corneum with acertain amount of impact determined to effectively pierce the skin withthe microprotrusions. The preferred applicator impacts the stratumcorneum with the microprotrusion member with an impact of at least 0.05joules per cm² of the microprotrusion member in 10 msec or less.

In accordance with one aspect of the present invention, a method isdisclosed for forming a plurality of microslits through the stratumcorneum through which an agent can be delivered or sampled. The methodinvolves providing a microprotrusion member having a plurality ofstratum corneum-piercing microprotrusions, and causing themicroprotrusions to impact the stratum corneum with an impact of atleast 0.05 joules per cm² of the microprotrusion member in 10 msec orless.

In accordance with another aspect of the present invention, a device isdisclosed for forming a plurality of microslits through the stratumcorneum through which an agent can be delivered or sampled. The deviceincludes an applicator having a stratum corneum contacting surface, anda microprotrusion member having a plurality of stratum corneum-piercingmicroprotrusions, the microprotrusion member mounted on the applicator,wherein the applicator, once activated, causes the microprotrusionmember to impact the stratum corneum under conditions of at least 0.05joules per cm² of microprotrusion member in 10 msec or less.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in greater detail with reference tothe preferred embodiments illustrated in the accompanying drawings, inwhich like elements bear like reference numerals, and wherein:

FIG. 1 is a side cross sectional view of an applicator device in aninitial configuration prior to cocking;

FIG. 2 is a side cross sectional view of the applicator device of FIG. 1in a cocked position with a patch retainer attached to the applicator;

FIG. 3 is a side cross sectional view of the applicator device of FIG. 1with the patch retainer of FIG. 2 after the piston has been released toapply the patch;

FIG. 4 is a perspective view of an alternative embodiment of anapplicator device;

FIG. 5 is a perspective view of a portion of one example of amicroprotrusion array;

FIG. 6 is a side sectional view of a pressure driven applicator device;and

FIG. 7 is a graph of dose M (in μg) of ovalbumin delivered over two timeperiods (5 seconds and 1 hour) from dry coated microprotrusions arraysapplied using manual finger pressure (non-hatched bars) and usingautomatic applicators in accordance with the present invention (hatchedbars).

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 illustrates an applicator device 10 for repeatable impactapplication of an array of microprotrusions to the stratum corneum. Theapplicator device 10 is configured to achieve a predefined andconsistent impact of a microprotrusion member including an array ofmicroprotrusions on the stratum corneum to provide acceptablepenetration of the stratum corneum with the microprotrusions. Inparticular, the applicator device 10 has been designed to optimize thepower per unit area of the impact to achieve effective penetration ofthe stratum corneum with the microprotrusions.

As will be described in further detail below, it has been determinedthat the applicator device 10 should deliver range of power per unitarea of a microprotrusion member for effective penetration of thestratum corneum. The range of power per unit area is represented as aminimum energy per unit area delivered to the skin site in a maximumamount of time.

One embodiment of the applicator device 10, as shown in FIGS. 1-3,includes a device body 12 and a piston 14 movable within the devicebody. A cap 16 is provided on the device body 12 for activating theapplicator to impact the stratum corneum with a microprotrusion member(not shown in FIG. 1). An impact spring 20 is positioned around a post22 of the piston 14 and biases the piston downward with respect to thedevice body 12. The piston 14 has a lower surface 18 which issubstantially planar or configured to a bodily surface. Upon activationof the applicator device the impact spring 20 moves the piston 14 andcauses a microprotrusion member, such as a transdermal patch containinga microprotrusion array to impact and pierce the stratum corneum.

FIG. 1 shows the piston 14 in an uncocked position, while FIG. 2 showsthe piston in the cocked position. When the applicator device is cocked,the piston 14 is pressed up inside the device body 12 and locked inplace by a locking mechanism. The locking mechanism includes a catch 26on the post 22 and a flexible finger 28 on the device body 12 having acorresponding latch 30. As the piston 14 is moved toward the device body12 compressing the impact spring 20, the catch 26 flexes the finger 28and snaps over the corresponding latch 30 of the flexible finger. Thecocking step may be performed by a single compression motion which bothcocks and locks the piston 14 in the cocked position.

FIG. 2 illustrates the applicator device 10 with the piston 14 in acocked configuration. As shown in FIG. 2, with the device in the cockedposition, the catch 26 and latch 30 on the piston 14 and device body 12are releasably engaged preventing downward motion of the piston in thedevice body.

FIG. 2 also illustrates a retainer ring 34 mounted on the device body12. The retainer ring 34 has a first end 40 which is configured tofriction fit onto the device body 12. A second end 42 of the retainerring 34 provides a stratum corneum contacting surface. A microprotrusionmember 44 including the microprotrusions is mounted between the firstand second ends 40, 42 of the retainer ring 34. The microprotrusionmember 44 is suspended in the retainer ring 34. The manner in which themicroprotrusion member 44 is mounted in the retainer ring 34 and thelocation of the microprotrusion member may vary. For example, themicroprotrusion member 44 may be positioned adjacent the second end 42of the retainer ring 34.

According to one example, the microprotrusion member 44 is connected byfrangible sections of base material to an annular ring of base materialwhich is adhered to the retainer ring 34. When the piston 14 ofapplicator device 10 is released, the microprotrusion member 44 isseparated from the retainer ring 34 by the downward force of the piston14. Alternatively, the microprotrusion member 44 may be releasablyattached to the piston 14 or positioned on the skin beneath the piston.

The retainer ring 34 is attached to the device body 12 after cocking ofthe piston 14. The retainer ring 34 is attached by a snap in connection,a bayonet fitting, or a slide on fitting which allows the retainer ring34 to slide on the device body 12 in a direction normal to the axis ofthe applicator.

The applicator device 10 has been described for use with amicroprotrusion member 44, such as a transdermal patch. A transdermalpatch useful with the present invention generally includes amicroprotrusion array, an agent reservoir, and a backing. However, theapplicator device 10 may also be used with a microprotrusion memberwithout an agent reservoir. In this case, the microprotrusion member isused as a pretreatment which is followed by the application or samplingof an agent with a separate device. Alternatively, the microprotrusionmember may incorporate the agent as a coating on the microprotrusions,e.g. for delivering a vaccine intradermally.

The activation of the applicator device 10 by releasing the lockingmechanism is performed by downward force applied to the applicator cap16 while the second end 42 of the retainer ring 34 is held against theskin with a hold down force. The cap 16 is biased upwards by a hold downspring 24 which is positioned between the device body 12 and the cap.The cap 16 includes a pin 46 extending downward from the cap. When thecap 16 is pressed downward against the bias of the hold down spring 24,the pin 46 contacts a ramp 48 on the flexible finger 28 moving theflexible finger outward and disengaging the latch 30 of the flexiblefinger from the catch 26. When the predetermined hold down force isachieved, the piston 14 is released and moves downward impacting thestratum corneum with the microprotrusion member 44. FIG. 3 illustratesthe applicator device 10 after the device has been activated and amicroprotrusion member has been impacted against the stratum corneum.

The hold down spring 24 is selected such that a predetermined hold downforce must be achieved before the applicator device 10 is activated. Thehold down force causes the stratum corneum to be stretched by thesurface 42 of the retainer ring 34 so that the skin is under optimaltension at the time the microprotrusion member 44 impacts the skin.

The hold down force applied by the hold down spring 24 is preferablyselected to cause the second end 42 of the retainer right 34 to apply atension to the skin in the range of about 0.01 to 10 megapascals (MPa),more preferably about 0.05 to 2 MPa. The hold down force with which theskin contacting surface 42 of the retainer ring 34 is held against theskin when the piston 14 is released, is preferably at least 0.5 kg, andmore preferably, at least 1.0 kg.

A balance between the hold down spring 24 and the impact spring 20allows the cocking of the piston 14 by pressing on the cap 16 withoutcausing the finger 46 to release the locking mechanism. In other words,upon application of a cocking force to the applicator device 10, theimpact spring 20 will be deflected prior to the deflection of the holddown spring 24.

The impact spring 20 is selected to apply a force to the piston whichachieves a predetermined impact of the microprotrusion member 44 againstthe stratum corneum. The microprotrusion member 44 is impacted with anenergy which provides a desired skin penetration with themicroprotrusions. The impact spring 20 is also preferably selected toachieve the desired skin penetration without exceeding an impact whichcauses discomfort to the patient.

The impact of the microprotrusion member against the stratum corneum isdetermined by the following features of the applicator device: 1) thedistance (x) the piston 14 travels from the cocked and locked position(shown in FIG. 2) to the skin; 2) the amount of compression in theimpact spring 20 when the piston 14 is in the cocked and lockedposition; 3) the rate (k) of the impact spring 20 as it moves from thecocked and locked position to the skin impacting position; 4) the time(t) in which the potential energy (PE) of the impact spring 20 isimparted as kinetic energy (KE) to the skin; 5) the mass (m) of themoving impact piston and patch with the microprotrusion array; 6) anyenergy loss (L) associate with friction or breakage of the frangibleconnections holding the patch on the retainer; and 7) the area (A) ofimpact. The impact is also effected by conditions external to theapplicator device including the configuration of the microprotrusionmember and the condition of the skin (e.g., stretched or unstretched) onimpact. These conditions external to the applicator device have beentaken into account in determining the desired impact power.

The power of impact (P) per unit area (A) of the microprotrusion arrayis defined as follows:P/A=(KE)/(A)(t)

-   -   wherein: PE=KE+L        PE=0.5(k)(x)²        KE=0.5(m)(v)²        P=(KE)/(t)        P/A=(KE)/(A)(t)

EXAMPLES

The following are examples of applicator systems having impact springswhich provide acceptable power per unit area for delivery of amicroprotrusion member, as tested on human skin. The applicator 10described earlier herein was configured with three different impactsprings having different spring constants and lengths as shown below.These three applicator/spring configurations where found to beacceptable for delivery of microblade arrays having the three differentareas listed below. The microprotrusion device delivered wassubstantially similar to the device illustrated in FIG. 5 havingmicroblades with lengths of about 250 μm.

Total Microblade spring spring Energy Energy/ array area Spring constant(K) length (L) Delivered Area 1 cm² #71512 9.3 lb/in 1.75 in 0.36 J 0.36J/cm² 2 cm² #71526  14 lb/in 1.75 in 0.63 J 0.32 J/cm² 3.3 cm²   #71527 12 lb/in 2.00 in 1.07 J 0.32 J/cm²

The impact spring 20 is preferably selected to deliver a minimum amountof energy of 0.05 Joules per cm², which is delivered in less than 10milliseconds (msec). A preferred amount of energy is a minimum of 0.10Joules per cm², which is delivered in less than 1 msec. A maximum amountof energy delivered by the impact spring 20 is about 0.3 Joules per cm².The maximum amount of energy delivered has been determined based on thebalance between the use of additional energy to achieve additional bladepenetration and a desire to prevent discomfort (e.g. pain and bruising)caused by impacting the stratum corneum with the microprotrusion member.

FIG. 4 illustrates an alternative embodiment of an applicator 80 havinga different shape and a release button 86 for manual activation.According to this embodiment, a user grasps a handle 82 of theapplicator device 80 and presses a lower end 84 of the device againstthe stratum corneum. Activation of the applicator device 80 is performedmanually by pressing the release button 86 and the amount of hold downforce is controlled manually and independently of the when the releasebutton 86 is pressed. The applicator 80 of FIG. 4 may include a holddown indicator on the applicator handle 82 which indicates to the user(e.g., by means of an audible, tactile, or visible signal) when thepredetermined hold down force has been achieved and the release button86 should be pressed.

The applicator devices 10, 80 according to the present invention havebeen described with respect to an upright orientation in which themicroprotrusion member 44 is applied from a piston side of the devicewhich is illustrated at the bottom of the devices in the figures. Itshould be understood that the applicator devices may be used in otherorientations.

While the applicator devices 10 and 80 are spring-loaded, it will beappreciated by those skilled in the art that other known energy sources(e.g., pressure, electricity, magnets and other biasing members besidescompression springs such as tension/extension springs and rubber bands)can be used in place of the spring 20 and are considered equivalentsthereof as long as such alternative energy source provides theprescribed minimum power at impact.

One example of a pressure driven applicator device is shown in FIG. 6.Pressure driven applicator 60 has a tubular body 61 with a recessed cap63. The recessed cap has a central orifice 64 through which is disposedrod 67 of piston rod unit 65. At the upper end of rod 67 is disposed apiston 66 which slidingly and sealingly engages the inner surface ofbody 61. As can be seen, the piston 66 also divides the interior spacewithin body 61 into an upper chamber 71 and a lower chamber 72. Rod 67also slidingly and sealingly engages the central orifice 64 in recessedcap 63. Disposed on the lower end of rod 67 is an impact head 68 whichis adapted to impact the skin-piercing microprotrusion member describedelsewhere herein against the patient's skin. To operate the applicator60, the piston 66 is moved from a position adjacent recessed cap 63 andslid upwardly towards orifice 69 by pressing on impact head 68. Aspiston 66 moves upwardly within the interior of body 61, air withinchamber 71 is expelled through orifice 69. Further, because of thesealing contact of the piston 66 with the inside surface of body 61 andthe sealing contact of the rod 67 with orifice 64, a partial vacuum isformed within chamber 72. When impact head 68 engages the lower surfaceof recessed cap 63, a sliding catch 74 is pressed through opening 73 inbody 61. Optionally, a second sliding catch 74′ is disposed in opening73′. Thus, the sliding catches 74 and 74′ act to hold the impact head 68against cap 63 against the force exerted by the partial vacuum withinchamber 72. Once secured by sliding catches 74 and 74′, themicroprotrusion member can be mounted on the lower surface of impacthead 68. Once this is done, the applicator 60 is placed against thepatient's skin with edge 62 contacting the skin. The sliding catch 74 isthen pulled out causing the impact head 68 to impact the mountedmicroprotrusion member against the skin, causing the microprotrusions topierce the skin.

Optionally, the orifice 69 may be eliminated. In such a configuration,the piston rod unit 65 is driven not only by a partial vacuum formedwithin chamber 72 but also a positive (i.e., above atmospheric) pressurewithin chamber 71.

FIG. 5 illustrates a portion of one embodiment of a microprotrusionmember for piercing the stratum corneum for use with the presentinvention. FIG. 5 shows a plurality of microprotrusions in the form ofmicroblades 90. The microblades 90 extend at a substantially 90° anglefrom a sheet 92 having openings 94. The sheet 92 may be incorporated inan agent delivery patch or an agent sampling patch which includes anagent reservoir and an adhesive for adhering the patch to the stratumcorneum. Examples of agent delivery and sampling patches whichincorporate a microprotrusion array are found in WO 97/48440, WO97/48441, WO 97/48442. The microprotrusion array of FIG. 5 without areservoir may also be applied alone as a skin pretreatment.

The term “microprotrusion” as used herein refers to very tiny stratumcorneum piercing elements typically having a length of less than 500 μm,and preferably less than 250 μm, which make a penetration in the stratumcorneum. In order to penetrate the stratum corneum, the microprotrusionspreferably have a length of at least 10 μm, more preferably at least 50μm. The microprotrusions may be formed in different shapes, such asneedles, hollow needles, blades, pins, punches, and combinationsthereof.

The term “microprotrusion member” as used herein refers to a memberincluding a plurality of microprotrusions for piercing the stratumcorneum. The microprotrusion member may be formed by cutting a pluralityof blades from a thin sheet and folding each of the blades out of theplane of the sheet to form the configuration shown in FIG. 5. Themicroprotrusion member may also be formed in other known manners, suchas by connecting multiple strips having microprotrusions along an edgeof each of the strips as disclosed in Zuck WO 99/29364 which isincorporated herein by reference. The microprotrusion member may includehollow needles which inject a liquid formulation.

Examples of microprotrusion arrays are described in U.S. Pat. No.5,879,326 issued to Godshall, et al., U.S. Pat. No. 3,814,097 issued toGanderton, et al., U.S. Pat. No. 5,279,544 issued to Gross, et al., U.S.Pat. No. 5,250,023 issued to Lee, et al., U.S. Pat. No. 3,964,482 issuedto Gerstel, et al., Reissue 25,637 issued to Kravitz, et al., and PCTPublication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO98/00193, WO 99/64580, WO 98/28037, WO 98/29298, and WO 98/29365, all ofwhich are incorporated herein by reference in their entirety.

The device of the present invention can be used in connection with agentdelivery, agent sampling, or both. In particular, the device of thepresent invention is used in connection with transdermal drug delivery,transdermal analyte sampling, or both. Examples of agents which may bedelivered include drugs and vaccines. An example of a body analyte whichmay be sampled is glucose. Transdermal delivery devices for use with thepresent invention include, but are not limited to passive devices,osmotic devices, pressure-driven devices, and electrotransport devices.Transdermal sampling devices for use with the present invention include,but are not limited to, passive devices, negative pressure drivendevices, osmotic devices, and reverse electrotransport devices. Thetransdermal devices of the present invention may be used in combinationwith other methods of increasing agent flux, such as skin permeationenhancers.

The device of the present invention may be used with a microprotrusionmember, such as a transdermal delivery or sampling patch having adhesivefor attaching the patch to the skin. Alternatively, the microprotrusionmember and a delivery or sampling patch may be two separate elementswith the microprotrusion member used for pretreatment prior toapplication of the delivery or sampling patch.

Example 1

Titanium microprotrusion embers comprising a circular sheet (sheet areawas 2 cm²) having microprotrusions with the shape and configurationshown in FIG. 5 (microprotrusion length of 360 μm, and a microprotrusiondensity of 190 microprotrusions/cm²) were coated with the model proteinvaccine ovalbumin. A 200 mg/mL aqueous coating solution offluorescein-tagged ovalbumin was prepared. For coating, themicroprotrusion members were immersed briefly in this solution, blowndry, and allowed to dry overnight at room temperature. Subsequentanalysis demonstrated that the microprotrusion members were coated withovalbumin at 200 to 250 μg/cm².

A study was perfomed in hairless guinea pigs (HGPs) to evaluateovalbumin absorption into the skin after short (5 second) application ofthe microprotrusion members. The system applied comprised a coatedmicroprotrusion member adhered to the center of a low densitypolyethylene (LDPE) backing with the acrylate adhesive (8 cm² disc). Inone group of five HGPs, the systems were applied with an impactapplicator. The impact applicator impacted the system against theanimals' skin with an impact energy of 0.42 J in less than 10 m sec andthe system was removed after 5 seconds contact with the skin. In asecond group of five HGPs, the system was applied to the skin using a 2kg/cm² manual pressure, held in place for 5 seconds, then removed. Inboth groups, penetration was similar as evidenced by good retention ofthe microprotrusions into the skin. Following removal of the system,residual drug was thoroughly washed from the skin and a 8 mm skin biopsywas taken at the location of the microprotrusion member application. Thetotal amount of ovalbumin delivered into the skin was determined bydissolving the skin biopsy sample in hyamine hydroxide(diisobutylcresoxyethoxyethyl) (dimethyl) benzylammonium hydroxyde, 1 Min ethanol, sold by J. T. Baker (NJ, USA) and quantitation performed byfluorimetry. Results showed that impact application resulted in anaverage delivery of 30.1 μg ovalbumin while only 6.6 μg of ovalbumin wasdelivered on average with manual application.

Example 2

A second experiment was performed with dry-coated ovalumin to comparedelivery following impact and manual application using a differenttitanium microprotrusion member and a longer application time. A 200mg/mL aqueous coating solution of fluorescein-tagged ovalbumin wasprepared. The microprotrusion members (microprojection length 214 μm, noretention feature, 292 microprojections/cm², 2 cm² disc) were immersedbriefly in the coating solution, blown dry and allowed to dry overnightat room temperature. Subsequent analysis demonstrated that themicroprotrusion members were coated with ovalbumin at 200 to 250 μg/cm².

The delivery study was perfomed in hairless guinea pigs (HGPs). Thesystem applied comprised a coated microprotrusion members adhered to thecenter of a LDPE backing with acrylate adhesive (8 cm² disc). In onegroup of five HGPs, microprotrusion member application was performedwith an impact applicator (0.2 J/cm² in less than 10 msec) and thesystem was removed after 5 seconds contact with the skin. In a secondgroup of five HGPs, the system was applied to the skin using a 2 kg/cm²manual pressure, held in place for 5 seconds, then removed. Twoadditional groups of hairless guinea pigs were treated as describedabove except that, following application, the system was left in contactwith the skin for 1 hour. Following removal of the system, residual drugwas thoroughly washed from the skin and a 8 mm skin biopsy was taken atthe location of the microprotrusion member application. The total amountof ovalbumin delivered into the skin was determined by dissolving theskin biopsy sample in hyamine hydroxide and quantitation performed byfluorimetry. The results of amount of ovalbumin delivered (M) for thetwo time periods (t) are presented in FIG. 7 and demonstrate that higherdelivery following impact application as compared to manual applicationis independent of the application time.

Examples 1 and 2 demonstrate that the higher amounts of ovalbumindelivered using impact application, as compared with manual application,is independent of the microprotrusion members design, the type ofcoating and the application time.

While the invention has been described in detail with reference to thepreferred embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made and equivalentsemployed, without departing from the present invention.

1. A device for forming a plurality of microslits through the stratumcorneum through which an agent can be delivered or sampled, comprising:an applicator having a contacting surface; and a microprotrusion memberhaving a sheet with a plurality of stratum corneum piercing microblades,the microprotrusion member being releasably mounted on said applicator,wherein said applicator, once activated, brings said contacting surfaceinto contact with said microprotrusion member in such a manner that saidmicroprotrusion member strikes the stratum corneum with an energy perunit area of at least 0.05 joules per cm² of microprotrusion member in10 milliseconds or less, wherein the microblades are coated with theagent.
 2. A device for forming a plurality of microslits through thestratum corneum through which an agent can be delivered or sampled,comprising: an applicator having a contacting surface; said applicatorbeing driven by an energy source selected from the group consisting of abiasing member, pressure, electricity and magnetism; and amicroprotrusion member having a sheet with a plurality of stratumcorneum piercing microblades, the microprotrusion member beingreleasably mounted on said applicator, wherein said applicator, onceactivated, brings said contacting surface into contact with saidmicroprotrusion member in such a manner that said microprotrusion memberstrikes the stratum corneum with an energy per unit area of at least0.05 joules per cm² of microprotrusion member in 10 milliseconds orless, and wherein the microblades are coated with the agent.
 3. A devicefor forming a plurality of microslits through the stratum corneumthrough which an agent can be delivered or sampled, comprising: anapplicator having a contacting surface; said applicator being driven byan energy source selected from the group consisting of a spring,pressure, electricity and magnetism; and a microprotrusion member havinga sheet with a plurality of stratum corneum piercing microblades, themicroprotrusion member being releasably mounted on said applicator,wherein said applicator, once activated, brings said contacting surfaceinto contact with said microprotrusion member in such a manner that saidmicroprotrusion member strikes the stratum corneum with an energy perunit area of at least 0.05 joules per cm² of microprotrusion member in10 milliseconds or less, and wherein the microblades are coated with theagent.
 4. A device for forming a plurality of microslits through thestratum corneum through which an agent can be delivered or sampled,comprising: an applicator having a contacting surface; said applicatorbeing driven by an energy source selected from the group consisting of aspring, pressure, electricity and magnetism; said spring being an impactspring and capable of applying an impact having a power of at least 0.05joules per cm² of microprotrusion member in 10 milliseconds or less; anda microprotrusion member having a sheet with a plurality of stratumcorneum piercing microblades, the microprotrusion member beingreleasably mounted on said applicator, wherein said applicator, onceactivated, brings said contacting surface into contact with saidmicroprotrusion member in such a manner that said microprotrusion memberstrikes the stratum corneum with an energy per unit area of at least0.05 joules per cm² of microprotrusion member in 10 milliseconds orless, and wherein the microblades are coated with the agent.
 5. A devicefor forming a plurality of microslits through the stratum corneumthrough which an agent can be delivered or sampled, comprising: anapplicator having a contacting surface; and a microprotrusion memberhaving a sheet with a plurality of stratum corneum piercing microblades,the microprotrusion member being releasably mounted on said applicator,wherein said applicator, once activated, brings said contacting surfaceinto contact with said microprotrusion member in such a manner that saidmicroprotrusion member strikes the stratum corneum with an energy perunit area of at least 0.05 joules per cm² of microprotrusion member in10 milliseconds or less, and wherein the microblades are coated with theagent.
 6. A device for forming one or more microslits through thestratum corneum through which an agent can be delivered or sampled,comprising: an applicator having a contacting surface; a microprotrusionmember having a sheet with a plurality of stratum corneum piercingmicroblades, the microprotrusion member being releasably mounted on saidapplicator, wherein said applicator, once activated, brings saidcontacting surface into contact with said microprotrusion member in sucha manner that said microprotrusion member strikes the stratum corneumwith an energy per unit area of at least 0.05 joules per cm² ofmicroprotrusion member in 10 milliseconds or less; and a hold downspring for achieving a hold down force required for device activation,and wherein the microblades are coated with the agent.
 7. A device forforming a plurality of microslits through the stratum corneum throughwhich an agent can be delivered or sampled, comprising: an applicatorhaving a contacting surface; a microprotrusion member having a sheetwith a plurality of stratum corneum piercing microblades, themicroprotrusion member being releasably mounted on said applicator,wherein said applicator, once activated, brings said contacting surfaceinto contact with said microprotrusion member in such a manner that saidmicroprotrusion member strikes the stratum corneum with an energy perunit area of at least 0.05 joules per cm² of microprotrusion member in10 milliseconds or less; and a hold down spring, and wherein themicroblades are coated with the agent.
 8. A device for forming aplurality of microslits through the stratum corneum through which anagent can be delivered or sampled, comprising: an applicator having acontacting surface; a microprotrusion member having one or more stratumcorneum piercing microprotrusions, the microprotrusion member beingreleasably mounted on said applicator, wherein said applicator, onceactivated, brings said contacting surface into contact with saidmicroprotrusion member in such a manner that said microprotrusion memberstrikes the stratum corneum with an energy per unit area of at least0.05 joules per cm² of microprotrusion member in 10 milliseconds orless; a hold down spring; and an indicator which indicates when apredetermined hold down force is applied to said applicator, and whereinthe microblades are coated with the agent.
 9. A device for forming aplurality of microslits through the stratum corneum through which anagent can be delivered or sampled, comprising: an applicator having acontacting surface; a microprotrusion member having a sheet with aplurality of stratum corneum piercing microblades, the microprotrusionmember being releasably mounted on said applicator, wherein saidapplicator, once activated, brings said contacting surface into contactwith said microprotrusion member in such a manner that saidmicroprotrusion member strikes the stratum corneum with an energy perunit area of at least 0.05 joules per cm² of microprotrusion member in10 milliseconds or less; a hold down spring; and an indicator whichindicates when a predetermined hold down force is applied to saidapplicator; wherein said indicator provides an audible, tactile, orvisible signal to indicate when said predetermined hold down force isapplied, and wherein the microblades are coated with the agent.
 10. Adevice for impacting a microprotrusion member, said microprotrusionmember having thereon a sheet with a plurality of microblades, saidmicroprotrusion member adapted to form a plurality of microslits throughthe stratum corneum through which an agent can be delivered or sampled,said device comprising: an applicator having a contacting surface; andsaid applicator adapted to cause said contacting surface to impact saidmicroprotrusion member in such a manner that said microprotrusion memberstrikes the stratum corneum with an energy per unit area of at least0.05 joules per cm² of microprotrusion member in 10 milliseconds orless, and wherein the microblades are coated with the agent.